The applicant's academic career demonstrates a long-term commitment to patient-oriented research, extensive expertise in the study of the role of the vascular endothelium in the regulation of peripheral vasomotor tone in patients with heart failure, and a successful record in mentoring fellows for careers in patient-oriented research. The career plan of the applicant is to continue expansion of research interests to studies of genetic epidemiology in heart failure, to strengthen existing and form new collaborative relationships with basic and clinical investigators at Yale, and to continue the successful mentoring program for young clinical investigators. The mentoring program consists of three key components: 1) intensive individualized training in patient-oriented research; 2) Yale University didactic programs on clinical trial design, data analysis, grant writing, and ethics; 3) critical review by a team of patient-oriented research experts. Continuation of the Midcareer Investigator Award in Patient-Oriented Research will provide critically needed protected time to achieve these career goals. Yale provides a strong institutional environment for support of the applicant's career development. The Department of Internal Medicine and Section of Cardiovascular Medicine at Yale have committed to protect 50% of the applicant's time for patient-oriented research and mentoring. The aim of the research plan is to characterize the role of genetic factors in non-familial chronic heart failure (CHF). Detection of gene effects in complex traits like CHF may be facilitated by characterization of intermediate phenotypes with quantitative physiological measurements relevant to the functional effects of specific candidate gene protein products. We propose to prospectively determine the relationship between common DNA variants in vascular regulatory genes and endothelium-dependent flow-mediated dilation of the brachial artery at rest and in response to transient homocysteine-induced oxidative stress in healthy control subjects and subjects with CHF. We hypothesize that common DNA variants in candidate genes that regulate metabolism of nitric oxide, reactive oxygen species, homocysteine and iron are associated with heterogeneity of vascular responses when adjusted for disease severity and other potential confounding clinical, biochemical and dietary factors. The proposed studies will advance applicant career development and provide new insight into pathophysiology of CHF.